Visualizing insulin actions on neuronal metabolism and function using fluorescent biosensors

胰岛素抵抗导致外周组织（例如肌肉和肝脏）和大脑无法 适当利用葡萄糖并产生ATP。这种情况在老年人中的患病率，以及 在与认知能力下降相关的几种病理中， 系统重要的是，大脑需要身体总能量输出的约20%，但仅包含有限的 能源储备。因此，大脑非常容易出现低血糖和低代谢状态， 发生在神经系统疾病中然而，胰岛素对能量代谢的复杂调节作用 和神经元内稳态仍然未知。前驱糖尿病或T2DM患者13表现出胰岛素 抵抗力和认知障碍。然而，尽管一些研究表明， 脑胰岛素抵抗和认知能力下降，胰岛素信号对脑能量稳态的作用， 认知表现仍然是一个谜。关于胰岛素的神经作用的机制研究已经被 仅限于培养细胞，忽略了神经元和星形胶质细胞之间的复杂相互作用， 能量平衡该应用程序的前提是基于胰岛素的综合观点 没有关于能量代谢的行动，但需要了解和制定干预措施， 糖尿病和其他多种影响认知健康的疾病的影响。这里提出的项目是 特别关注于推进我们对胰岛素调节神经元能量代谢的基本理解， 及其对神经元兴奋性、神经传递和行为的影响。我们会发现 大脑切片中神经元兴奋性和代谢的读数，这是一个保留复杂3D模型的模型。 天然脑组织的组织和电路。我们假设糖酵解和氧化磷酸化 在神经元中，胰岛素信号直接调节，这导致能量代谢的增加， 钙清除、神经传递和突触可塑性。提出了以下目标：目标1： 阐明胰岛素信号在神经元能量代谢中的作用机制。目标2：描述角色 神经元胰岛素信号对海马细胞内钙动力学和突触可塑性的影响。目的 3.研究神经元胰岛素抵抗对学习记忆的影响。拟议的研究将形成 向NIH申请R01所需的基础和初步数据集中在胰岛素对 健康和疾病中的神经元代谢。

Insulin resistance produces a failure of peripheral tissues (e.g. muscle and liver) and the brain to appropriately utilize glucose and generate ATP. The prevalence of this condition in aging individuals, as well as in several pathologies associated with cognitive decline, represents a major challenge for the health care system. Importantly, the brain requires ~20% of the total energy output of the body but contains only limited energy reserves. As a result, the brain is highly vulnerable to hypoglycemia and hypometabolic states that occur in neurological disorders. However, the role of insulin on the complex regulation of energy metabolism and homeostasis in neurons remains unknown. Patients with prediabetes or T2DM13 exhibit both insulin resistance and cognitive impairment. However, despite several studies suggesting an association between brain insulin resistance and cognitive decline, the role of insulin signaling on brain energy homeostasis and cognitive performance remains an enigma. Mechanistic studies on the neuronal actions of insulin have been limited to cultured cells that ignore the complex interactions between neurons and astrocytes that are critical to energy homeostasis. The premise of this application is based on the fact that an integrated view of insulin action on energy metabolism is not available but is required to understand and develop interventions for the effects of diabetes and multiple other diseases that impact cognitive health. The project proposed here is specially focused on advancing our basic understanding of insulin regulation of neuronal energy metabolism, and its consequences for neuronal excitability, neurotransmission, and behavior. We will detect simultaneous readouts of neuronal excitability and metabolism in brain slices, a model that preserves the complex 3D organization and circuitry of native brain tissue. We hypothesize that glycolysis and oxidative phosphorylation in neurons are directly regulated by insulin signaling, which result in an increase in energy metabolism, calcium clearance, neurotransmission, and synaptic plasticity. The following aims are proposed: Aim 1: Define the mechanisms of insulin signaling on energy metabolism in neurons. Aim 2: Characterize the role of neuronal insulin signaling on cytosolic calcium dynamics and synaptic plasticity in the hippocampus. Aim 3: Investigate the role of neuronal insulin resistance on learning and memory. The proposed studies will form the foundation and preliminary data necessary for an R01 application to NIH focused on insulin effects on neuronal metabolism in health and disease.